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Phase 1 Clinical Trials: Frequently Asked Questions

Patricio Ledesma

1 September, 2020

What is a phase 1 clinical trial?

A phase 1 clinical trial is a clinical study in humans that seeks to evaluate the safety (toxicity) of a new drug (or combination of drugs) and its maximum tolerated dose (MTD) to be used in subsequent stages of clinical development.

Why are phase 1 clinical trials important?

Phase 1 clinical trials are tremendously important for pharma and biotech companies because they test how safe a new drug is patients. 

These studies are critical in early phases of drug development and, in addition to exploring the toxicity of the new compound, they are used to evaluate and define the best dosing scheme to be used in later phase 2 and 3 trials. 

Phase 1 trials are the first treatment tests in human subjects so their results are of utmost importance for the chances of future commercialization of the novel drug.

What is the main general goal of a phase 1 clinical trial?

The main purpose of phase 1 clinical trials is to demonstrate that patients tolerate well the new drug under investigation. 

The toxicity data (adverse effects) derived from these studies are used to characterize the safety profile of the new medicinal product. 

Phase 1 studies are also utilized to determine the most adequate dose and test different administration schemes of the compound. 

Furthermore, phase 1 trials are used to observe preliminary signs of drug efficacy against the disease being treated.

Is a phase 1 clinical trial the same as “first in human” study?

In general, all “first in human” trials are phase 1 clinical trials. However, not all phase 1 trials are “first in human” since a drug is normally tested in more than one phase 1 study. In other words, the “first in human” concept refers to the very first trial in which a drug is evaluated in patients.

Do phase 1 clinical trials always imply the use of a new drug?

Not necessarily. Some phase 1 trials are conducted with new drugs under development but others are done, for example, with combinations of drugs that are already in the market. 

Thus, medicines already approved and commercialized can be tested together in new combination therapies and in different diseases, and such scenarios would be considered in the context of a phase 1 trial.

Are phase 1 trials performed in healthy volunteers or patients with diseases?

Phase 1 clinical studies are conducted in both healthy volunteers and ill patients. Depending on the type of drug both types of trials can be performed. 

For instance, phase 1 trials in oncology will recruit patients affected by cancer to assess preliminary signs of efficacy for the benefit of the participants.

What are the main challenges of phase 1 trials and what errors should be avoided?

Phase 1 clinical trials pose a number of challenges. Correct endpoints, well-defined populations, subject enrollment potential, and solid trial management capabilities are very important.

Meaningful endpoints

Endpoints are the variables utilized to measure the safety and efficacy of a drug tested in a clinical trial. For example, a typical endpoint in oncology studies is overall survival (OS); essentially the time from patient enrollment until death.

The primary endpoint of a trial must be relevant for the patient, clinically meaningful, and objectively measured without bias.

The easy part about phase 1 trials is that these studies, by definition, always assess the safety of the new treatment. Then, a typical phase 1 study in oncology will have the evaluation of toxicity and the maximum tolerated dose (MTD) as primary endpoints.

Nevertheless, phase 1 trials may include secondary or exploratory endpoints and these are important too. Defining irrelevant, inadequate endpoints in the study protocol may mean that the trial results will not be useful to assess interesting aspects of the new therapy.

To ensure relevant endpoints, trial sponsors should obtain advice from clinical experts in the specific disease they are targeting.

You may read the article “Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Populations” for further information on phase 1 trial design considerations, particularly in cancer.

Well-defined populations

The good definition of the eligible patient population is another key aspect when designing a phase 1 trial.

An excessively heterogeneous patient population is not the best strategy, since heterogeneity (patients with too different characteristics) will decrease the meaning of certain endpoints. 

This is particularly important in cancer trials with different tumor subtypes. Although the primary endpoint of a phase 1 study is not efficacy, sponsors should target specific histologies with very specific inclusion criteria, in order to ensure consistent outcomes and conclusions towards subsequent phase 2 trials.

Subject enrollment potential

Patient enrollment is not typically a major issue in phase 1 trials, since these types of studies enroll a small number of subjects.

Nevertheless, still in phase 1 trials, guaranteeing sufficient enrollment potential is important, especially in trials testing drugs in rare diseases.

How can sponsors ensure enrollment potential in infrequent diseases? 

Enrollment feasibility questionnaires should be carefully designed and reviewed in depth before study initiation, asking sites to be realistic about their recruitment estimates.

Trial management capabilities

Phase 1 trials will require a smaller number of patients and sites, in comparison with larger studies (phase 2 and 3). However, phase 1 studies have particular operational challenges.

The operational complexity of phase 1 trials is due to the need of monitoring the safety of patients very closely. Since the drug being tested is new, and toxicity is the main concern, patients have to be supervised more exhaustively, and this implies the dedication of additional resources.

Moreover, phase 1 trials usually include the collection of biological samples (like several blood draws for pharmacokinetics tests), so this makes the management of the trial more demanding. 

In order to take care of the administrative, regulatory, and technical complexities of phase 1 studies, sponsors should select appropriate Contract Research Organizations (CROs).

What protocol design considerations are critical in phase 1 clinical trials?

Some of the most critical aspects of a phase 1 clinical trial protocol are the inclusion/exclusion criteria, the treatment scheme, and the procedure to determine the maximum tolerated dose (MTD).

The inclusion/exclusion criteria defines the characteristics of the subjects to be treated in the trial.

The treatment scheme describes how the study drugs are administered, proposing the experimental drug administration dose and sequence with the best chances of success. 

A key part of phase 1 protocols is the strategy to determine the maximum tolerated dose (MTD) of the experimental treatment. This requires the definition of dose-limiting toxicities (DLTs).

How many sites are normally required in a phase 1 clinical trial?

Phase 1 trials normally require few hospitals to recruit the intended number of patients. Depending on the recruitment potential of each site, a typical phase 1 trial may involve somewhere between 1-5 sites (sometimes more). 

Given that phase 1 studies have demanding procedures and special tests, particular sites with dedicated phase 1 units may be selected. 

Conducting the study with less sites may play in favor of better operational control and increased quality.

How many patients are normally recruited in a phase 1 clinical trial?

As a general rule, phase 1 studies require a low number of patients, typically 12-20 subjects. The exact number of patients will depend on the dose levels to be tested (in order to determine the MTD). Phase 1 trials do not need a formal sample size calculation (in contrast with phase 2 and 3 studies).

What is the duration of a phase 1 clinical trial?

The duration of a phase 1 trial mainly depends on the number of patients to be treated, the recruitment rate, and the treatment scheme. In average, phase 1 trials in cancer may have enrollment periods of 6-10 months.

How much does a phase 1 clinical trial cost?

Please refer to the articleHow Much Do Phase 1 Clinical Trials Cost in the United States?to learn about clinical trial expenses.

Which clinical research organization (CRO) should I choose for my phase 1 clinical trial?

Please refer to the article “How to Select a Clinical Research Organization (CRO)” to get advice on CRO selection.

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